To describe the pathology and clinical features of a novel lysosomal myopathy associated with biallelic variants in CLN8

Ceroid lipofuscinosis is a rare cause of lysosomal storage disease in muscle and until now described only in neuronal ceroid lipofuscinosis 3. CLN8 encodes an endoplasmic reticulum protein essential for lysosomal biogenesis. Deficiency of CNL8 cause ceroid lipofuscinosis 8, which has been associated with progressive epilepsy with mental retardation with onset at 5 to 10 years of age followed by a progressive decline of cognitive skills. Another known form is late-infantile CLN8 with onset at 2 to 7 years of age and a more severe course.

We have investigated a woman who presented with focal to bilateral tonic seizures at 40 years of age. The patient was diagnosed with epilepsy and started treatment. In parallel, a diffuse muscle weakness and muscle pain was noted, increasing after seizures. The patient described photosensitivity and was assessed in the dermatology and rheumatology clinics due to skin discolorations. She had increased CK and myoglobin levels and on the suspicion of dermatomyositis a muscle biopsy was performed. The biopsy material was investigated by standard methods for muscle pathology including electron microscopy and genetic investigation was performed by genome sequencing.

Muscle biopsy showed vacuolar myopathy with atrophic muscle fibers and increased connective tissue. There was a marked increase of lysosomes as revealed by LAMP2 staining and extensive lysosomal storage of curvilinear-like material on electron microscopy. The storage material was auto fluorescent and was present also in vessel walls. Blood lymphocytes showed typical fingerprint inclusions. Genetic analysis revealed biallelic CLN8 (NM_018941.4) variants c.511C>T; p.P171S and c.536T>A; p.L179H.

Vacuolar myopathy with characteristic morphological features of lysosomal ceroid lipofuscin storage disease in muscle and lymphocytes may occur as an adult-onset form of CLN8.